排序方式: 共有14条查询结果,搜索用时 171 毫秒
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Smith CC Wang Q Chin CS Salerno S Damon LE Levis MJ Perl AE Travers KJ Wang S Hunt JP Zarrinkar PP Schadt EE Kasarskis A Kuriyan J Shah NP 《Nature》2012,485(7397):260-263
Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts. 相似文献
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Hovatta I Tennant RS Helton R Marr RA Singer O Redwine JM Ellison JA Schadt EE Verma IM Lockhart DJ Barlow C 《Nature》2005,438(7068):662-666
Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders--such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder--these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes. Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety-like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behaviour. 相似文献
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Mehrabian M Allayee H Stockton J Lum PY Drake TA Castellani LW Suh M Armour C Edwards S Lamb J Lusis AJ Schadt EE 《Nature genetics》2005,37(11):1224-1233
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RNA profiling can be used to capture the expression patterns of many genes that are associated with expression quantitative trait loci (eQTLs). Employing published putative cis eQTLs, we developed a Bayesian approach to predict SNP genotypes that is based only on RNA expression data. We show that predicted genotypes can accurately and uniquely identify individuals in large populations. When inferring genotypes from an expression data set using eQTLs of the same tissue type (but from an independent cohort), we were able to resolve 99% of the identities of individuals in the cohort at P(adjusted) ≤ 1 × 10(-5). When eQTLs derived from one tissue were used to predict genotypes using expression data from a different tissue, the identities of 90% of the study subjects could be resolved at P(adjusted) ≤ 1 × 10(-5). We discuss the implications of deriving genotypic information from RNA data deposited in the public domain. 相似文献
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我们在[7]中引进了Gorenstein平坦模。本文将这类模的刻画推广到任意n-Gorenstein环上,并利用这类模刻画了n-Gorestein环。而且,我们证明了任意n-Gorenstein环上Gorenstein平坦预包络的存在性,并证得得这种环关于Gorenstein平坦模的内射类的整体维数至多为n-2,当n≤1时,该整体维数为零。 相似文献
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An integrative genomics approach to infer causal associations between gene expression and disease 总被引:2,自引:0,他引:2
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Genetics of gene expression surveyed in maize,mouse and man 总被引:111,自引:0,他引:111
Schadt EE Monks SA Drake TA Lusis AJ Che N Colinayo V Ruff TG Milligan SB Lamb JR Cavet G Linsley PS Mao M Stoughton RB Friend SH 《Nature》2003,422(6929):297-302